Journal club 26.11.06

Defensins mediate skin inflammation and itch in psoriasis

Sharan Kumar Balaji1, Qin Zheng2, Huasheng Yu3, Joann Truong1, Luchiano Giovanni Benjamin Fernando1, Yining Liu1, Clara Shin3, Wenqin Luo3, Xinzhong Dong4 and

Xintong Dong1

Psoriasis is an inflammatory skin condition that features marked upregulation of keratinocyte-derived antimicrobial
peptides, particularly !-defensins. Yet, the functions of these peptides in skin inflammation remain
unclear. In this study, we used a defensin cluster-knockout mouse to evaluate the potential roles of defensins
as neuroimmune modulators in psoriasis. Deletion of the defensin gene cluster (Def conditional knockout) in
keratinocytes significantly attenuated imiquimod-induced psoriatic inflammation, with reduced hyperkeratosis,
erythema, scaling, and expression of inflammatory cytokines and chemokines. In addition, the Def conditionalknockout
mice exhibited reduced neutrophil and IL-17→ TCR”# T-cell infiltration in the psoriatic skin, indicating
a critical role of defensins in amplifying T helper 17 immunity. Behavioral analysis further revealed that
the loss of defensins reduced psoriatic itch, and we showed that human !-defensin 2 directly activated smalldiameter
Mrgpra3 neurons to elicit robust scratching. Overall, our study revealed that !-defensins play an
important role in mediating inflammation and itch associated with psoriasis by activating neutrophils, type 17
immune response, and pruriceptive sensory neurons, suggesting defensin signaling as a potential therapeutic
target in psoriasis.